Epidemiological studies have established a correlation between Type 2 diabetes and increased cancer risk and prognosis. Breast cancer is one of the most common cancers occurring in women. In women with Type 2 diabetes breast cancer is more common and has a worse prognosis, independent of obesity. The mechanisms involved in the increased cancer risk in Type 2 diabetes have not been defined. Determining the mechanisms involved in this process requires the use of animal models that can be manipulated to study the role of the hyperinsulinemia and the insulin receptors (IRs) and insulin-like growth factor-1 receptors (IGF-1Rs) that mediate insulin's effect. We have generated a mouse model of Type 2 diabetes, by introducing a dominant-negative IGF-1R in skeletal muscle that initially leads to severe insulin resistance, followed by the development of Type 2 diabetes. The mice are not obese and this enables us to study the factors related to Type 2 diabetes without the confounding factors involved in obesity. The mammary glands of the diabetic mice have more extensive epithelial growth compared to non-diabetic mice. Induction of mammary tumors by DMBA and the PyVmT oncogene in the diabetic mice resulted in an increased incidence and more aggressive behavior of the tumors compared to the control non-diabetic mice. We hypothesize that the hyperinsulinemia is the cause of the increase in tumor development and that the effect is mediated via the insulin receptors (and IR/IGF-IR hybrid receptors) in the mammary epithelium and in the tumors that develop. We propose to: 1. Define the exact mechanisms causing the increased growth of mammary epithelial cells in the diabetic mice, 2. Examine the mammary epithelium and the tumors for the type of insulin and IGF- 1 receptors expressed, 3. Determine whether the increased tumor incidence is associated with larger tumors and increased metastases, 4. Determine which receptors mediate these events and the signaling pathways involved, 5. Knock-down the IRs and IGF-1Rs in cancer cells and the diabetic mice to determine the effect on tumorigenesis and metastases. 6. Determine whether reversal of the insulin resistance and hyperinsulinemia affects tumor development growth and metastases The results of these studies will provide further insights into our understanding of the factors involved in the increased risk of breast cancer in diabetes and may lead to new opportunities for targeted therapy. PUBLIC HEALTH RELEVANCE: The results of these studies will provide further insights into our understanding of the factors involved in the increased risk of breast cancer in diabetes and may lead to new opportunities for targeted therapy.